JPH0269478A - Quinolonecarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is lower alkyl or alkenyl; R<2>-R<4> are H or lower alkyl). EXAMPLE:1-Ethyl-6-fluoro-7-(5-isopropylidene-2,4-dioxo-1,3-oxazolidin- 3-yl)-1,4- dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester. USE:A drug having antibacterial activity against Gram-negative bacteria. PREPARATION:A compound of formula I wherein R<2> is R<2>' can be produced by condensing a 7-aminoquinolinecarboxylic acid derivative of formula II (R<2>' is lower alkyl) with an O-chlorocarbonyl-alkenylglycolic acid ester of formula III (R<5> is R<2>') in the presence of a base in an organic solvent and heating or refluxing the resultant compound of formula IV in an organic solvent in the presence of a base. The obtained compound can be converted to another compound of formula I wherein R<2> is H by selective hydrolysis with iodomethylsilane.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel quinolone carboxylic acid derivatives having antibacterial activity. More specifically, the present invention is represented by the general formula (wherein R1 represents a lower alkyl group or an alkynyl group, and R2, R:l, and R4 each independently represent a hydrogen atom or an alkyl group). The present invention relates to a novel quinolone carboxylic acid derivative characterized by having a fluorine atom at the 6-position of the quinolone ring and an alkylidene oxazolidinedione ring at the 7-position.

[Conventional technology]

Quinolone carboxylic acid-based synthetic antibacterial agents were developed as oral treatments for urinary tract infections that are effective against aerobic gram-negative bacteria, and in recent years, quinolones called new quinolones, which are active against not only aerobic gram-negative bacteria but also gram-positive bacteria, have been developed. Carboxylic acid antibacterial agents have been developed [for example, Diagnosis and Treatment, 11.1313 (1986), Clinical and Microbiology, 14
．． 169 (19B?)].

[Problem that the invention seeks to solve]

However, new quinolone drugs also have problems such as the occurrence of side effects in the central nervous system and not necessarily good absorption properties. Furthermore, it has recently been pointed out that some bacteria may already be resistant to commercially available new quinolones such as norfloxacin. An object of the present invention is to provide a quinolone carboxylic acid derivative that has excellent antibacterial activity, has few side effects, and has good absorbability.

[Means to solve the problem]

As a result of intensive studies to solve the above problems, the present inventors succeeded in synthesizing a new quinolone carboxylic acid derivative having an alkylidene oxapridine dione ring at the 7th position, which is difficult to synthesize using conventional methods. It was confirmed that the compound has antibacterial activity against Gram-negative bacteria, leading to the completion of the present invention.

The present invention relates to a quinolone carboxylic acid derivative represented by the general formula (wherein R1, RZ, R3, and R4 have the same meanings as above).

In the formula, examples of the lower alkyl group represented by R1 include straight chain or branched alkyl groups such as methyl group, ethyl group, propyl group, butyl group, isobutyl group, pentyl group, 3-pentyl group, and hexyl group. be able to. Also,
Examples of the alkynyl group include propargyl group, 1-methylpropargyl group, 1.1=dimethylpropargyl group, 1-
Examples include alkynyl groups such as ethylpropargyl group, 2-butynyl group, 3-butynyl group, 2pentynyl group, and 3-pentynyl group. Examples of R2 include a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group. Furthermore, R3 and R4 are exemplified independently of each other by a hydrogen atom or a straight or branched alkyl group such as a methyl group, an ethyl group, a propyl group, an isobutyl group, a butyl group, an isobutyl group, a hexyl group, an octyl group, etc. Can be done.

Next, the method for producing the quinolone carboxylic acid derivative represented by the general formula (1) of the present invention will be explained in detail.

The quinolone carsonic acid derivative represented by general formula (1) can be synthesized, for example, according to the route shown below.

(I゛) That is, a 7-aminoquinolonecarboxylic acid derivative represented by -maximum (2) (wherein R1 represents the same meaning as above and R2' represents a lower alkyl group) and the general formula (3
) (In the formula, R3 and R4 represent the same meanings as above, and R5
represents a lower alkyl group. ) by a condensation reaction with a 0 chloride power carbonyl alkenyl glycolic acid ester derivative, -maximum (4) (R', R desk R co, R4
, and R5 have the same meanings as above, and a carbamate ester derivative represented by a) can be obtained. This reaction is usually carried out in a suitable organic solvent in the presence of a base. As the base, aromatic amines such as pyridine, lutidine, and pyrimidine, and tertiary amines such as triethylamine, dimethylaniline, and N-methylmorpholine can be used. Although the reaction can be carried out in a neutral organic solvent, it is preferable to carry out the reaction using the base used as a solvent since the yield is good.

Next, by treating the carbamate ester derivative represented by the -i formula (4) with a base, the general formula (1') can be easily obtained.
A 7-(alkylidenedioxoxazolidin-3-yl)quinolonecarboxylic acid ester derivative represented by the formula (wherein R', R, R, R3, and R4 have the same meanings as above) can be obtained.

This is the substituent I in maximum (1) above? The quinolone carboxylic acid derivative of the present invention is a quinolone carboxylic acid derivative in which z is a lower alkyl group. The reaction is preferably carried out in a conventional organic solvent under heating or reflux. As the base, basic inorganic compounds such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, etc. can be used. The amount of base used is generally sufficient for catalyst (2). As the organic solvent, aromatic solvents such as benzene, toluene, chlorobenzene, and dichlorobenzene, ether solvents such as tetrahydrofuran and dimethoxyethane, and solvents such as acetonitrile and dimethylformamide can be used.

Next, the ester portion of the quinolone carboxylic acid ester represented by the general formula (1゛) thus obtained is selectively hydrolyzed using trimethyl iodide to obtain the general formula (1'') (in the formula, 7-(alkylidenedioxoxazolidin-3-yl)quinolonecarboxylic acid derivatives represented by R1, R3 and "represent the same meanings as above." The quinolone carboxylic acid derivative of the present invention is a quinolone carboxylic acid derivative in which the group R2 is a hydrogen atom.

The reaction can be carried out in a solvent such as carbon tetrachloride, chloroform, acetonitrile, dimethylbormamide, etc. at a temperature ranging from room temperature to a high temperature that does not decompose the compound.

The general formula of the present invention that can be synthesized in this way (
Typical quinolone carboxylic acid derivatives shown in 1) are shown in Table 1.

Table-t Quinolonecarboxylic acid derivatives. The 7-aminoquinolonecarboxylic acid derivative (2), which is a raw material compound, can be synthesized, for example, by the following route.

^C 80 That is, 2-fluoro-5-nitroacetanilide obtained by acetylation of 2-fluoro-5-nitroaniline is reduced in the presence of a platinum oxide catalyst and converted to 3-acetylamino-4-fluoroaniline. did. Next, this product was condensed with ethoxymethylene diethyl malonate (3
-acetylamino-4-fluorophenyl)aminomethylene diethyl malonate, and was cyclized under heating to give ethyl 6-fluoro-twoacetylamino-4-hydroxyquinoline-3-carboxylate. Next, this product was reacted with a lower alkyl halide or an alkynyl halide in the presence of a base to introduce a lower alkyl group or an alkynyl group onto the nitrogen atom at the 1-position. Finally, the 7-aminoquinolone derivative → can be produced by deacetylation under acidic conditions.

In addition, 〇-chlorinated silvonylalkenyl glycolic acid ester derivative 4) is a 2-hydroxy-3-alkenoic acid ester derivative represented by -max (in the formula, R3, R4, and R5 have the same meanings as above). and phosgene gas or lily.

It can be produced by reaction with formic acid trichloromethyl ester (phosgenda 2-imer).

Hereinafter, the present invention will be explained in more detail with reference to Examples, Reference Examples, and Test Examples. Further, the melting point and spectral data of the obtained quinolone carboxylic acid derivative are shown in Tables 2 and 3.

Example 1 - Ethyl-ethyl-6-fluoro-amino-1,4-dihydro-4-oxoquinoline-3-carboxylate (0
, 40 g, 1.4 mmol) in a pyridine solution (20 m
2) 2-carbonyloxy-3methyl chloride under water cooling
After adding an ether solution (5 ml) of methyl 3-butenoate (0.79 g, 3.8 mmol), the mixture was stirred at room temperature for 10 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, 2N hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ether was added to the obtained yellow oil to precipitate a solid, which was collected by filtration to obtain 1-ethyl-6-fluoro-7-(N-(1
″-methoxycarbonyl-2′-methyl-2°-propenyl)oxycarbonyl)amino-1,4-dihydro-
A colorless solid of ethyl 4-oxoquinoline-3-carboxylate (0.50 g, yield 82%) was obtained. 'If-NMR(
CDCh, TMS, 6ppm): 8.51(s, I
II), 8.39 (d, III, Jny=7.6Hz
), 8.24 (d, In.

JPF=I-1-7tlz)+7.65(br,s,
IN), 5.30(s, 1)1), 5.22(s,
IH), 5.14 (s, III), 4.40 (q,
2H, J=6.9Hz), 4.28(q, 2H+J=
7.0Hz) + 3.74(s, 3H), 1.82(
s, 311), 1.48 (t, 3H, J=6.911
z), 1.35 (t, 311.J=7.0IIz).

Example 2 1-ethyl-6fluoro-7-amino-1,4-dihydro-4-oxoquinoline- was obtained by scratching in the same manner as in Example 1.
Ethyl 3-carboxylate (0.65g, 2.0mmol)
and methyl 2=carbonyloxychloride-3-methyl-3-propenoate (0.88 g, 4,2 mmol I) to form 1-ethyl-6-fluoro-7(N-(
Yellow oil of ethyl 1'-methoxycarbonyl-2'-methyl (2'-butenyl)oxycarbonyl)amino-14dihydro-4-oxoquinoline-3-carboxylate (0
, 79 g, yield 86%).

This product was used in the next reaction (see Example 13) without being purified.

Example 3 Ethyl 1-propargyl 6-fluoro-tuamino-1,4-dihydro-4oxoquinoline-3-carboxylate (0.86 g, 3.0+ nm
ol) and 2-chlorinyloxy-3-methyl-3-
■-Propargyl-6-fluoro-7 (N
-(1'-methoxycarbonyl-2'-methyl-21-
A yellow oil (1.22 g, yield 85%) of ethyl (butenyl)oxycarbonyl)amino 1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained. This product was used in the next reaction (see Example 14) without being purified.

Example 4 1-ethyl-6-fluoro-7-(N-(1'-methoxycarbonyl-2'-methyl-2'-propenyl)oxycarbonyl)amino-1,4-dihydro 4-oxoquinoline-3- Ethyl carboxylate (0,50g-, 1,2
Anhydrous sodium acetate (0.5 g) was added to a toluene solution (3 h+j) of 1 mmol), and the mixture was heated under reflux for 5 hours.

After the reaction was completed, it was concentrated under reduced pressure. Next, water was added, extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow crystals were purified by silica gel column chromatography (elution solvent: chloroform/ethyl acetate = 2/1) and then recrystallized from ether-hexane to obtain pure 1-ethyl-6-fluoro-7.
-(5-isopropylidene-2,4-dioxo-1,3
-oxazolidin-3-yl)-1,4-dihydro-4
Colorless crystals (0.20 g, yield 43%) of ethyl -oxoquinoline-3-carboxylate [Compound No. 1] were obtained.

Example 5 1-ethyl-6-fluoro-7(55ec-butylidene-2,4-dioxo-1,3-oxazolidin-3-yl) -1,4-dihydro-4-oxoquinoline-3-
Colorless crystals (0,4
5 g, yield 63%).

Example 6 By the same operation as in Example 4, l-ethyl-6fluoro7-(N-(1°-methoxycarbonyl-2'-methyl-2'-phthynyl)oxycarbonyl)amino-1
, 4-dihydro-4-oxoquinoline-3-carboxylate (0.79 g, 1.8 mmol) from Example 4
1-propargyl-6-fluoro-
7-(N-(1"-methoxycarbonyl-2'-methyl-2'-butenyl)oxycarbonyl)amino-1,4
-dihydro-4-oxoquinoline-3-carboxylic acid ethyl (1.22 g, 2.6 mmol) to 1-propargyl-6-fluoro-7-(5-5ee-butylidene-
2,4-dioxo-13-oxazolidin-3-yl)
Colorless crystals of ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate [Compound No. 3] (0.40 g
, yield 36%).

Example 7 Pure 1-ethyl-6-fluoro-7-(5-isopropylidene-2,4-thio-1-so-13-oxazolidin-3-yl)14-dihydro- Colorless crystals (0.15 g, yield 80%) of 4-oxoquinoline-3-carboxylic acid [Compound No. 4] were obtained.

Example 8 1-ethyl-6-fluoro-7-(5-isopropylidene-2,4-dioxo-1,3-oxazolidine-3-
-1,4-dihydro-4-oxoquinoline-3
-Ethyl carboxylate (0.20g, 0.5mmol)
Add trimethylsilane iodide (1,4d, 10 mmol) to a carbon tetrachloride solution (30 relatives) and heat at 55-60 °C.
and stirred for 48 hours. After the reaction was completed, a 10% aqueous sodium thiosulfate solution was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the mixture was concentrated under reduced pressure. The obtained colorless solid was treated in the same manner as in Ether-Salt Example 7 to obtain 1-ethyl-6-fluoro-7(5-
sec-butylidene-2,4-dioxo-13-oxazolidin-3-yl)-L4 ethyl dihydro-4-oxoquinoline-3-carboxylate (0,10+ng, 0
．． 3 mmol of trimethyl iodide (0.8 mff
1.40 mmol), 1-ethyl-6-fluoro-7 (5-5ec butylidene-2,
4-dioxo-1,3-oxazolidin-3-yl) i
, colorless crystals of 4-dihydro-4-oxoquinoline-3-carboxylic acid [Compound No. 5] (0.08 g, yield 85%
) was obtained.

Example 9 By the same operation as in Example 7, 1-propargyl-6-
Ethyl fluoro-7(5-sec-butylidene 2,4-dioxo-1,3-oxazolidin-3-yl)14-dihydro-4-oxoquinoline-3-carboxylate (0,
20g, 0.5mmol) of trimethylsilane iodide 0
．． 4ml, lommol),
1-Propargyl-6-fluoro-7(5-see-butylidene-2,4-dioxo-1,3-oxazolidin-3-yl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid [Compound No. 6] colorless crystals (0,
15 g, yield 77%) was obtained.

Reference Example 1 AC 2-Fluoro-5 was added to acetic anhydride (130ml) under water cooling.
-Nitroaniline (25.0g, 0.160mol
) and then stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, and the precipitate was collected by filtration and thoroughly washed with ether to obtain yellow crystals of N-acetyl-2-fluoro-5-nitroaniline (30.3 g, yield 96%). Ta.

'It-NMR (CDCh, TMS, δppm):
9.03 (dd, ill, JHr=6.3Hz), 8
．． 07-7.82 (n+, III), 7.23 (dd
, III, Jgr=10.511z) 2.19(s, 3
11).

Reference example 2 N-acetyl-2-fluoro-5-nitroaniline (6
, 01g, 30.0mo+) in ethanol solution (120
Platinum oxide (0.3 g) was added to mR), and hydrogen gas was added at room temperature and pressure until absorption stopped. After the reaction was completed, platinum oxide was filtered off, concentrated under reduced pressure, and the precipitate was collected by filtration. Next, recrystallize from ethanol-ethyl acetate to obtain pure 3-
Colorless needle crystals of acetylamino-4-fluoroaniline (
(4.72 g, yield 92%).

+1-NMR (CDCI: 1.TMs, δppm)
: 7.67 (dd, l11), 7.31 (br,
s, 1II), 6.82 (dd, IH+JHp□12
．． 3tlz) + 6.16-6.41 (m 1ll),
3.56 (br, S, 211), 2.14 (s, 3
11).

Reference example 3 Ac ll 3-acetylamino-4-fluoroaniline (3,09
Add diethyl ethoxymethylene malonate (4.40 g, 20.3 mmo+) to 18.41 of
Heated at 0°C for 1.5 hours. After the reaction was completed, unreacted diethyl ethoxymethylenemalonate was distilled off under reduced pressure, and the precipitate was collected by filtration. Next, colorless crystals of pure diethyl N-((3'-acetylamino)-4'-fluoro)phenyl)aminomethylenemalonate (6,01 g, yield 98%) were recrystallized from ether-hexane. Obtained. 'If-
NMR (CDCh, TMS, δppm): 8.
52and8.38(each S+total 1B
) + 8.26 (dd, lH, JHy・6.0l12)
.

7.64 (br, s, 111), 7.15 (dd, I
II, Jny=11. IIIz), 6.80(m, 1
tl), 4.29 and 4.37(each q
, total 411. J=7.0fiz), 2.2
6(!1.3)1), 1.34 and 1.39(
each L, tota1611, J=7.0IIz
).

Reference Example 4 Colorless crystals (2.98 g, yield 57%) of ethyl mino-4-hydroxyquinoline-3-carboxylate were obtained.

+1-NMR (DMSO-d, TMS, δppm
): 10.16 (br, s, III).

8.67 (d, III, JxF=7.211z), 8
．． 55(s, III), 7.91(d, ltl.

Jur□12.611Z)+4.28(Q, 211.
J=7.111z)12.22(s,311)1.3H
t, 311. J=7.1tlz).

IR (KBr, cm-'): 3460.30
20.1?10.1690゜m, p, > 300°C6 Reference Example 5 N-[(3''-acetylamino)-4゛-fluoro)phenyl)aminomethylene diethyl malonate (6, old g
, 17.9 mmol) in diphenyl ether solution (3
0 mj was heated at 250°C for 1.5 hours. After the reaction was completed, the precipitate was allowed to stand at room temperature overnight, and the precipitate was collected by filtration and thoroughly washed with chloroform.
Ethyl chloride acetylamino-4-hydroxyquinoline-3-carboxylate (1,46 g, 5.0 mmo
+) dissolved in DMF? &(60d) is ethyl iodide (0,
87 g, 5.5 mmol) and anhydrous potassium carbonate (0.7
7g.

5.8 mmol) was added thereto, and the mixture was stirred at room temperature for 48 hours. After the reaction was completed, the precipitate was removed and concentrated under reduced pressure. The obtained brown oil was purified by silica gel column chromatography (elution solvent: chloroform/ethyl acetate = 1/1) to obtain pale yellow crystals. This product was further recrystallized from chloroform-hexane to obtain pure 1-ethyl-6-
Fluoro-2acetylamino)-1,4-dihydro-
Colorless crystals of ethyl 4-oxoquinoline-3-carboxylate (1.14 g).

A yield of 71% was obtained. '11-11MR (C11-1
l, TMS, δppm): 8.83 (d, LH,
JHF□7.211z), 8.51(s, 1!l),
8.23(d, IIl, L+y=11.71(z),
7.91(br,s+1)1), 4.42(q,2
H, J=7.0Hz), 4.28(q, 2H, J=7
．． 1Hz), 2.33(s, 31(), 1.56(
t.

3H, J = 7.0 IIz), 1.40 (t, 3H, J
=7. l11z).

IR (XBr, cm-'): 3440,30
50.1705.1680,1615゜Shin, p, 1
97-199°C.

Reference Example 6 Ethyl lowfluoro-7-acetylamino-4-hydroxyquinoline-3-carboxylate (2,98 g).

10, Ommol) in [1MI' solution (120 ml)
D. Prohargyl bromide (1.35g, 11.Ommol
), potassium iodide (1.33g, 11.Ommol
), and anhydrous potassium carbonate (1,53g, 11.O
mmol) and stirred at room temperature for 48 hours. After the reaction was completed, the precipitate was removed and concentrated under reduced pressure. The obtained brown oil was filtered by IJ gel column chromatography (Yoshikawa solvent: chloroform/ethyl acetate = 1/1) to obtain pale yellow crystals. This thing is also ether-
Pure 1-propargyl-6- by recrystallization from hexane
Fluoro-twoacetylamino-1,4-dihydro-4
-Colorless crystals of ethyl oxoquinoline-3-carboxylate (
2.15 g, yield 65%) was obtained. 'H-NMR (CD
C13, TMS.

δppm): 8.94(d, 11(, J=5.4H
z), 8.67 (s, 1) 1), 8.27 (d, L
H, JHr=11.7H2), 7.76(br, s, 1
8), 4.95 (d, 2H.

J=2.311z), 4.43(q, 2B, J=7.
1Hz), 2.67 (t, 111.J=2.3Hz)
, 2.35 (s, 311), 1.43 (t, 3H,
J=7.111z).

IR (KBr, vcm-'): 3440.30
50.2100.1725°1680, 1615°m, p, 180-183°C0 Reference Example 7 1-Ethyl-6-fluoro-toacetylamino-1,
Ethyl 4-dihydro-4-oxoquinoline-3-carboxylate (0.66 g, 2.0 mmol) in ethanol? @
Concentrated hydrochloric acid (0.5 ml) was added to the liquid (25 ml), and the mixture was heated under reflux for 3 hours. After the reaction was completed, a 5% aqueous solution of hydrogen carbonate was added, and the mixture was extracted with chloroform. Next, the organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the precipitate was collected by filtration. This product was recrystallized from chloroform-ethanol to obtain pure 1-ethyl-6-fluoro-tuamino-1,4-dihydro-4-oxoquinoline-3-
Colorless crystals of ethyl carboxylate (0.46 g, yield 82%
) was obtained.

'II-NMR (CDCl2-CD30D, TMS,
δppm) 78.56 (s, III).

7.97 (d, 111.JHr=11.7H2), 7.
07 (d, IH, JHF□6.311z).

4.44 (q, 2H, J, 7.1Hz), 4.36 (
q, 211. J=7.2Hz), 1.54(L, 3t
l, J=7.1Hz), 1.40(t, 311.J=
7.2Hz).

IR (KBr, vcm-'): 3490.3320
．． 3020. 1720゜1640゜, p, 280~2B2 °C Reference Example 8 By the same operation as in Reference Example 8, ■-propargyl 6-
fluorophoreacetylamino-1,4-dihydro-4
-Ethyl oxoquinoline-3-carboxylate (0,65g
, 2. colorless crystals of ethyl l-propargyl 6-fluoro-tuamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.53 g,
A yield of 93% was obtained. 'H-NMR (CDCI3CDz
OD, TMS, δppm): 8.68 (s, LH)
, 7.94 (d, IH, J.

=11.6Hz), 7.00(d,III,Jgr=
4.611z), 5.02(d, 2H, J=2.1H
z), 4.39 (q, 21.J=7.0Hz), 3
．． 37 (br, s, 211).

2.84 (d, III, J=2.1Hz), 1.40
(t, 3H, J=7.0Hz).

IR (KBr, vcm-'): 3500.33
30.3110.2120°1?15.1640°m, p, >300'C.

Reference Example 9 Methyl 2-hydroxy-3-methyl-3-butenoate (]
, 776g12. Ommol) and chloroformic acid trichloromethyl ester (1.5mL 12.Ommol)
Triethylamine (2 ml, 15.0 mmol) was added to a toluene solution (50 ml) of the mixture under water cooling, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, water was added, extracted with ether, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, it was concentrated under reduced pressure to obtain a yellow oily substance (1,9
0 g, 77%). 'H-NMR (CDCI 3
7M5. δppm): 5.39 (s, 1!l),
5.24 (s, IH), 5.20 (sIll), 3
．． 40 (s, 3H), 1.80 (s, 311) [R(
neat, cm-'): 2990.2970
．． 1782.1755゜Reference Example 10 By the same operation as in Reference Example 2, methyl 2-hydroxy-3-methyl-pentenoate (1.30 g, 9.0 mm
o I) and chloroformic acid trichloromethyl ester (
1.0 mR, 8, Ommol) to obtain a yellow oily substance (1.50 g, yield 80%) of methyl 2-carbonyloxy-3-methyl-3-pentenoate. 'II-N
MI? (CDCI3. TMS, δppm):
5.77 (m, il+), 5.40 (s, 1).

3.4Hs, 311L 1.66 (d, 311), 1
．． 64(d, 311).

IR (neat, cm-'): 2990.2
970.1780.1755゜Pharmacological Effect Test Example I C Antibacterial Spectrum] Antibacterial activity was measured using the Japanese Society of Chemotherapy's hrcifill.
This was carried out by the agar plate dilution method according to the standard method.

That is, a bacterial solution cultured at 37°C for 118 hours was diluted with an enrichment medium to 106 cFU/ml, and using a microblunter MIT-P (Sakuma Seisakusho),
Approximately 5 μl was inoculated onto the agar 'Lm ground containing the medicine Bajl and incubated at 37°
After culturing for 18 hours, antibacterial activity was measured. Drugs are 50%
acetic acid) and dissolved in 8 liquids. The concentration of the drug was determined to be the highest concentration for the test bacterial strain, which was not affected by acetic acid. Table 4 shows the results of determining the antibacterial activity as Wll+.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) (In the formula, R^1 represents a lower alkyl group or an alkynyl group, and R^2, R^3, and R^4 are mutually (independently represents a hydrogen atom or a lower alkyl group) A quinolone carboxylic acid derivative represented by: